Radiation therapy (RT)-induced cardiopulmonary injury, usually manifest as shortness of breath, is a major source of morbidity, and limits the delivery of RT for thoracic tumors. The physiologic determinants of RT-induced cardiopulmonary injury are not fully understood. In prior funding periods, we defined the relationship between changes in regional lung perfusion and changes in pulmonary function tests and symptoms. However, we also demonstrated that current methods to predict such RT-induced injury are suboptimal. In separate clinical studies, we have shown that RT causes reductions in regional myocardial perfusion that are correlated with abnormalities in heart wall motion and ejection fraction. The present proposal aims to simultaneously study RT-induced changes in lung and heart function and quantify their impact on global cardiopulmonary function. Animal and human data suggest that RT-induced heart and lung injury act together to cause cardiopulmonary dysfunction. Further, new conformal RT methods (e.g., intensity modulated RT, radiosurgery), often expose large portions of the lung and heart to diverse RT doses and fraction sizes. The impact of dose and fraction size on the pathogenesis of clinically significant lung and heart injury is not fully known. The current proposal builds on our prior work in the context of evolving clinical practice. We will simultaneously study RT-induced heart and lung injury in patients receiving modern conformal RT for lung cancer. We will prospectively determine the time, dose, and fraction-size dependence of RT-induced changes in regional lung perfusion (Aim 1), and regional heart perfusion/function (Aim 2). Heart and lung perfusion/function will be assessed with nuclear medicine and magnetic resonance imaging. We will quantify the relationship between RT-induced changes in regional lung perfusion, regional heart perfusion/function, and associated changes in global cardiopulmonary function (e.g. exercise testing) (Aim 3). This project is first to comprehensively evaluate both the lung-based and heart-based dosimetric and physiologic determinants of RT-induced cardiopulmonary injury. This information will lead to algorithms that accurately predict the risk of cardiopulmonary injury, facilitate the design of safer 3D dose distributions, and thus improve patient care.